The nasal route of drug administration has long been used where local action of drug is anticipated such as in rhinitis treatments. Recently, various studies were carried out on intranasal drug administration that is expected to have systemic effects because a) the nasal mucosa has a well developed vascular network and is thus histologically advantageous for drug absorption; b) drugs absorbed through the nasal mucosa can avoid first-pass metabolism in the gastrointestinal tract and liver; c) it is self-administrable and painless.
Interesting results obtained by those studies include a particularly preferred embodiment of a rapid-acting and prolonged-acting intranasal composition, which combines a base that is water-absorbing and water-insoluble and has 90% (w/w) or more of particles with a diameter in the range of 10 to 100 μm, and a base that is water-absorbing and gel-forming and has 90% (w/w) or more of particles with a diameter in the range of 50 to 350 μm (see Patent Document 1). It is clear from the Examples of Patent Document 1 that the formulation of 60 to 95% (w/w) hydroxypropyl cellulose (a water-absorbing and gel-forming base) and crystalline cellulose (a water-absorbing and water-insoluble base) does not change drug persistence, but shows immediate drug absorption as compared with crystalline cellulose base alone.
In another particularly preferred embodiment, an intranasal composition with improved drug absorbance is proposed. The composition is a combination of a water-absorbing and water-insoluble base that has 90% (w/w) or more of particles with a diameter in the range of 10 to 250 μm, and a water-absorbing and gel-forming base that has 90% (w/w) or more of particles with a diameter in the range of 10 to 50 μm. Patent Document 2 states that particles of 150 μm or more shall be actively used as a water-absorbing and water-insoluble base such as crystalline cellulose or the like. According to the Examples of Patent Document 2, when compared with crystalline cellulose base alone, a higher maximum drug level in blood is achieved if crystalline cellulose (a water-absorbing and water-insoluble base) is combined with 5 to 40% (w/w) hydroxypropyl cellulose (a water-absorbing and gel-forming base).
Furthermore, an intranasal insulin preparation proposed by the present applicants is also known. The preparation uses as a carrier, a crystalline cellulose aggregate in which 85% (w/w) or more of the particles have a cribriform particle diameter within the entire or partial range of 20 to 60 μm. The particles are substantially the same as those used in the present invention. The present applicants succeeded in improving insulin absorption with the preparation (see Patent Document 3).
[Patent Document 1] Japanese Patent Application Kokai Publication No. (JP-A) H9-291026 (unexamined, published Japanese patent application)
[Patent Document 2] JP-A H10-59841 (corresponding to EP-A1-943326)
[Patent Document 3] WO 03/004048A1 (corresponding to EP-A1-1413311)